Dataset Information

Consecutive mutational events in a TSHR allele of Arab families with resistance to thyroid stimulating hormone.

ABSTRACT: Our laboratory identified six distinct inactivating TSHR gene mutations in Arab tribes living in Israel. We recently reported three nucleotide substitutions in exon 3 producing p.[L89L;Q90P] and one in exon 9 of the same allele producing p.P264S in Family A. Family B, reported herein, harbors the identical mutation in exon 3 only. We set to determine whether the mutations have common ancestral origin.Coding regions of the TSHR were sequenced and flanking microsatellite markers spanning 5.3 cM were used for haplotyping.Two siblings of Family B were compound heterozygous for TSHR gene mutations. The paternal allele contained the exon 3 mutation and the maternal allele harbored a mutation in exon 10 (p.L653V). We investigated the possibility of a founder effect with subsequent mutational events for the presence of the same exon 3 mutation in different families. The haplotype of the allele harboring the exon 3 mutation in Family B was identical to that of Family A, also harboring the exon 9 mutation on the same allele, indicating that the latter occurred subsequently. The ancestral wild-type TSHR was present in Family B, suggesting that the mutation in exon 3 was also new in the history of that population.It is more likely that two consecutive mutational events occurred on the ancestral wild-type allele instead of a recombination bringing exon 3 and exon 9 mutations together on the same allele. New mutational events contribute to the high prevalence of TSHR mutations in this population in addition to a founder effect and limited gene pool due to inbreeding.

SUBMITTER: Sriphrapradang C

PROVIDER: S-EPMC3286805 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Consecutive mutational events in a TSHR allele of Arab families with resistance to thyroid stimulating hormone.

Sriphrapradang Chutintorn C German Alina A Dumitrescu Alexandra M AM Refetoff Samuel S

Thyroid : official journal of the American Thyroid Association 20120207 3

<h4>Background</h4>Our laboratory identified six distinct inactivating TSHR gene mutations in Arab tribes living in Israel. We recently reported three nucleotide substitutions in exon 3 producing p.[L89L;Q90P] and one in exon 9 of the same allele producing p.P264S in Family A. Family B, reported herein, harbors the identical mutation in exon 3 only. We set to determine whether the mutations have common ancestral origin.<h4>Methods</h4>Coding regions of the TSHR were sequenced and flanking micros ...[more]

PMID: 22313426

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Project description:Domestic chickens are less fearful, have a faster sexual development, grow bigger, and lay more eggs than their primary ancestor, the red junglefowl. Several candidate genetic variants selected during domestication have been identified, but only a few studies have directly linked them with distinct phenotypic traits. Notably, a variant of the thyroid stimulating hormone receptor (TSHR) gene has been under strong positive selection over the past millennium, but it's function and mechanisms of action are still largely unresolved. We therefore assessed the abundance of the domestic TSHR variant and possible genomic selection signatures in an extensive data set comprising multiple commercial and village chicken populations as well as wild-living extant members of the genus Gallus. Furthermore, by mean of extensive backcrossing we introgressed the wild-type TSHR variant from red junglefowl into domestic White Leghorn chickens and investigated gene expression, hormone levels, cold adaptation, and behavior in chickens possessing either the wild-type or domestic TSHR variant. While the domestic TSHR was the most common variant in all studied domestic populations and in one of two red junglefowl population, it was not detected in the other Gallus species. Functionally, the individuals with the domestic TSHR variant had a lower expression of the TSHR in the hypothalamus and marginally higher in the thyroid gland than wild-type TSHR individuals. Expression of TSHB and DIO2, two regulators of sexual maturity and reproduction in birds, was higher in the pituitary gland of the domestic-variant chickens. Furthermore, the domestic variant was associated with higher activity in the open field test. Our findings confirm that the spread of the domestic TSHR variant is limited to domesticated chickens, and to a lesser extent, their wild counterpart, the red junglefowl. Furthermore, we showed that effects of genetic variability in TSHR mirror key differences in gene expression and behavior previously described between the red junglefowl and domestic chicken.

Project description:BACKGROUND:Overt thyroid dysfunction has been associated with adverse obstetric outcomes. However, less is known regarding subclinical hypothyroidism or thyroid autoimmunity and their relationship to pregnancy complications. OBJECTIVE:The purpose of this study was to examine the association between prepregnancy anti-thyroid antibodies and subclinical hypothyroidism and preterm delivery, gestational diabetes mellitus, and preeclampsia. STUDY DESIGN:We conducted a secondary analysis of a prospective cohort of 18- to 40-year-old women with 1-2 previous pregnancy losses (n=1193) who participated in a multicenter randomized, placebo-controlled trial of low-dose aspirin. Prepregnancy levels of thyroid-stimulating hormone, free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibody were measured. Relative risks and 95% confidence intervals were estimated with the use of generalized linear models with adjustment for age and body mass index. RESULTS:Among women with an ongoing pregnancy of >20 weeks estimated gestational age, there was no association between prepregnancy thyroid-stimulating hormone level (>2.5 vs ?2.5 mIU/L) and preterm delivery (adjusted relative risk, 0.77; 95% confidence interval, 0.40-1.47), gestational diabetes mellitus (adjusted relative risk, 1.28; 95% confidence interval, 0.54-3.04), or preeclampsia (adjusted relative risk, 1.20; 95% confidence interval, 0.71-2.04). Similarly, among women with thyroid antibodies, there was no increase in the likelihood of preterm delivery (relative risk, 1.26; 95% confidence interval, 0.65-2.45), gestational diabetes mellitus (relative risk, 1.33; 95% confidence interval, 0.51-3.49), or preeclampsia (relative risk, 1.02; 95% confidence interval, 0.54-1.92), compared with women without these antibodies. CONCLUSION:Among women with 1-2 previous pregnancy losses, subclinical hypothyroidism and thyroid autoimmunity were not associated with an increased risk of preterm delivery, gestational diabetes mellitus, or preeclampsia. These data support current recommendations that low-risk asymptomatic women should not be screened routinely for thyroid dysfunction or autoimmunity.

Dataset Information

Consecutive mutational events in a TSHR allele of Arab families with resistance to thyroid stimulating hormone.

Publications

Consecutive mutational events in a TSHR allele of Arab families with resistance to thyroid stimulating hormone.

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